This application relates to compositions for treatment of differentiation antigen-dependent cancers and to methods of using such compositions. The invention utilizes compositions containing xenogeneic differentiation antigens, which are associated with cancers to provide effective therapy.
Differentiation antigens are tissue-specific antigens that are shared by autologous and some allogeneic tumors of similar derivation, and on normal tissue counterparts at the same stage of differentiation. Differentiation antigens have been shown to be expressed by a variety of tumor types, including melanoma, leukemia, lymphomas, colorectal carcinoma, breast carcinoma, prostate carcinoma, ovarian carcinoma, pancreas carcinomas, and lung cancers. For example, differentiation antigens expressed by melanoma cells include Melan-A/MART-1, Pmel17, tyrosinase, and gp75. Differentiation antigen expressed by lymphomas and leukemia include CD 19 and CD20/CD20 B lymphocyte differentiation markers). An example of a differentiation antigen expressed by colorectal carcinoma, breast carcinoma, pancreas carcinoma, prostate carcinoma, ovarian carcinoma, and lung carcinoma is the mucin polypeptide muc-1. A differentiation antigen expressed by, for example, breast carcinoma is Her2 (synonyms: Her2/neu, ECBB2, ErbB2, c-erb-2), which is a gene coding for a tyrosine kinase receptor that is a member of the family of epidermal growth factor receptors (De Maria et al., 2005). Over expression of Her2 has been demonstrated in mammary gland tumors of both the cat (Winston et al., 2005) and the dog (Rungsipipat et al., 2008). Winston et al. (2005) used existing assay methods (HERCEPTEST™, Dako USA, Carpinteria, Calif.; NCL-CB11, Novocastra, Newcastle, UK) to successfully grade levels of Her2 expression on feline mammary tumors as 0=minimal/absent, 1=weak, 2=moderate, or 3=intense. The HERCEPTEST™ and NCL-CB11 assays identified 27 and 23 cats respectively, out of 30 examined, as having grade 2 or 3 Her2 expression in mammary tumor samples.
In addition to successfully grading levels of Her2 over expression in feline mammary tumors, Winston et al. (2005) used the HERCEPTEST™ to detect low levels of Her2 expression in normal feline epithelial tissues and cell types including: hair follicle, mammary gland, gastric pit, salivary gland duct, renal cortical and medullary tubules, colonic and small intestinal crypt, brain, pancreatic duct and islets, splenic macrophages, adrenal cortex, hepatocytes, and testicular Leydig's cells. Expression of Her2 has been documented on a range of human epithelial cell types including gastro-intestinal, respiratory, reproductive, urinary, skin, mammary and placenta (Press et al., 1990). These findings indicate that the expression of Her2 is common in a range of tissue types of humans and cats. The finding of Her2 over expression in dog mammary tumors suggests this species would share expression characteristics identified in humans and cats. Existing assays and reagents can serve as tools to screen expression levels of Her2 in companion animal cancers in order to justify treatment with the Her2 cancer vaccine.
Unfortunately, in most cases, the immune system of the individual is tolerant of such differentiation antigens, and fails to mount an effective immune response. Several technologies have been considered to address this challenge: (cytokines as genetic adjuvants (Chang et al., 2004), xenogeneic vaccination (Pupa et al., 2005), electrotransfer (Quaglino et al., 2004), combination with chemotherapy (Bernhardt et al., 2002). Although results were encouraging, greater efficacy was required for these approaches to be considered a key component of a first-line therapeutic strategy. Further, recent findings indicate both antibody and cell-mediated immunity are required for tumor eradication post immunization, perhaps explaining, in part, the lack of success in the field (Orlandi et al., 2007). Therefore, for the treatment of cancers where the tumor expresses differentiation antigens therefore, it would be desirable to have a method for stimulating a therapeutically effective immune response against the differentiation antigen in vivo. It an object of the present invention to provide such a method.